This program investigates the effects of the radiosensitizer misonidazole in fractionated radiotherapy and will attempt to determine optimal conditions for its use. The studies will be conducted under conditions analogous to those encountered in human radiotherapy and will employ the types of radiation and drug schedules used clinically. Specifically, we will study the combined effects of misonidazole and fractionated radiotherapy in a number of tumor lines and in normal tissues in the WAG/Rij rat. We will attempt to distinguish hypoxic cytotoxicity from hypoxic cell radiosensitization and to determine what drug-radiation schedules optimize these effects. The ultimate goal is to provide information that will aid in the interpretation of the current Phase II misonidazole trials and in the development of Phase III trials. The tumor lines tested will include the BA1112 rat sarcoma; the normal tissues tested will be skin (a rapidly proliferating tissue) and kidney (a non-proliferating tissue). The experiments will attempt to mimic clinical trials by using multiple small drug injections in the rat to simulate the long serum half-life found in humans and by using long multi-fraction schedules. The studies will use both conventional and unconventional regimens and will enable us to distinguish between the effects of misonidazole and the effects of altering radiation schedules.